Congestive heart failure is an extremely serious affliction. Heart failure (HF) is not a specific disease, but rather a compilation of ailments and symptoms, all of which are caused by an inability of the heart to appropriately increase cardiac output during exertion. HF may be caused by chronic hypertension, ischemia, tachyarrhythmias, infarct or idiopathic cardiomyopathy. The cardiac diseases associated with symptoms of congestive heart failure include dilated cardiomyopathy, restrictive/constrictive cardiomyopathy, and hypertrophic cardiomyopathy. HF has a great impact on the quality of life; the sympathetic nervous system is placed into a state of hyperexcitablity leading to a loss of heart rate variability and rate responsive mechanisms in the heart. The ability of the heart to relax is impaired resulting in elevated filling pressures, pulmonary congestion and low exercise tolerance. These are just a few of the side effects. The classical symptoms of the disease include shortness of breath, edema, and overwhelming fatigue. As the disease progresses, the lack of cardiac output may contribute to the failure of other body organs, leading to cardiogenic shock, arrhythmias, electromechanical dissociation, and death. The disease afflicts millions of individuals globally in a given year; in the USA alone there are about 400,000 new cases, 1 million hospital admissions, and $8 billion cost of care.
The treatment of severe cardiac dysfunction and decompensated heart failure may include inotropic drug therapies such as dobutamine. Although these agents may be beneficial in specific settings, they require administration of a drug, often by intravenous route, with systemic side effects and the time-consuming involvement of skilled clinicians. Electrical stimulation therapies are attractive alternatives because implanted or external devices may administer them very shortly after dysfunction appears or worsens and because their actions may be confined to the heart.
The mechanical contraction of the heart is initiated by the spread of an electrical wavefront through the cardiac tissue. This cardiac excitation-contraction coupling is closely linked to the regulation of calcium both outside and inside the myocardial cell. Electrical depolarization of cardiac myocyte results in a small amount of calcium entry into the myocyte through the L-type calcium channels. This small calcium influx causes a calcium induced calcium release from the sarcoplasmic reticulum (SR), an internal cellular structure that stores calcium. The SR released calcium binds with the myocyte actin and myocin, leading to mechanical cell shortening (contraction). The calcium is then sequestered back into the SR, resulting in removal from the actin and myocin and relaxation of the myocyte. Electrical therapies such as post extrasystolic potentiation (PESP) and nonexcitatory electrical stimulation are thought to interact with the cardiac myocyte calcium handling by enhancing SR calcium uptake and L-type calcium influx, respectively.
Delivering stimulation during the refractory period of the cardiac cycle is a type of non-excitatory stimulation (NES). NES has been observed to cause release of catecholamines such as norepinephrine within the tissue of the heart, potentially contributing to an observed increase in increased contractility of the cardiac tissue. NES may also alter calcium influx from the intra-cellular space into the cardiac myocyte, which could increase the amount of calcium available for muscles contraction both directly and through greater SR calcium uptake and subsequent release. Whatever the mechanism, application of NES has been observed to increase pressure or flow, potentially leading to fewer symptoms of heart failure, and improved exertional capacity. NES employs one or more pulses applied shortly after a sensed depolarization or delivered pacing pulse and before the resulting ventricular contraction occurs. These NES pulses are delivered during the refractory period of the cardiac tissue such that they do not result in another mechanical contraction or electrical depolarization.
Another type of electrical stimulation can be provided during the nonrefractory period of the cardiac cycle to enhance cardiac performance. This type of paired and coupled stimulation of heart tissue results in an additional electrical depolarization and, when appropriately timed, results in post extrasystolic potentiation (PESP). The additional depolarization, coming shortly after a first depolarization, is likely not associated with a sizable mechanical contraction. The contractility of subsequent cardiac cycles is increased as described in detail in commonly assigned U.S. Pat. No. 5,213,098. One possible mechanism of PESP is thought to depend on calcium cycling within the myocytes. The early extrasystole tries to initiate calcium release from the sarcoplasmic reticulum (SR) too early and as a result does not release much calcium. However, the SR continues to take up further calcium until the next electrical depolarization, resulting in enhanced SR calcium uptake and SR release on the next depolarization, leading to a more rigorous mechanical contraction.
Another known treatment for HF patients involves using atrioventricular (AV) synchronous pacing systems, including DDD and DDDR pacing devices, cardiac resynchronization therapy (CRT) devices, and defibrillation systems, to treat certain patient groups suffering heart failure symptoms. Dual chamber pacing and defibrillation systems generally pace or sense in both the right atrium and right ventricle to synchronize contractions and contribute to ventricular filling. Cardiac resynchronization devices extend dual chamber pacing to biventricular pacing to achieve better filling and a more coordinated contraction of the left and right ventricles. These pacing therapies result in greater pulse pressure, increased dP/dt, and improved cardiac output. These pacing systems may also include atrial and ventricular defibrillators or other therapies for tachyarrhythmias. As a direct result of a tachycardia or as a sequela, cardiac function may deteriorate to the point of greatly reduced cardiac output and elevated diastolic pressure. Rapid termination of tachycardias prevents worsening of heart failure.
Prior art systems have not achieved a comprehensive therapy regimen that coordinates these mechanisms in a manner that is most effective without some degree of initiating potential arrhythmia with delivering a stimulation therapy in or around the non-refractory period to achieve PESP and/or NES. Delivery of electrical stimulation as the heart tissue is becoming non-refractory can trigger a tachyarrhythmia. This is particularly true if multiple high-amplitude pacing pulses are utilized. A second factor may be a shift in the magnitude of resulting potentiation or refractory interval due to the course of disease or medication. These may lead to unacceptable levels of potentiation performance, or loss of effect altogether. Therefore, readily obtaining the appropriate timing parameters associated with this type of therapy is essential.
The above-referenced '098 patent discloses the use of PESP in a manner that utilizes one or more sensors and signal processing circuitry to control timing parameters. For example, sensed physiologic signals are used to control the frequency or number of heart cycles between the delivery of one or more additional non-refractory pacing pulses. More specifically, a first sensor such as a ventricular or arterial blood pressure or flow sensor is employed to monitor the performance of the heart and to develop a cardiac performance index (CPI). A second sensor such as an oxygen saturation sensor positioned in the coronary sinus is employed to monitor cardiac muscle stress and develop a cardiac stress index (CSI). CPI and CSI are used to govern PESP stimulation application and timing to balance performance and stress. The disclosed PESP stimulator may be incorporated into a dual chamber pacing system with or without physiologic rate control (e.g., DDD).
Another problem associated with PESP is that the added ventricular depolarization may cause the loss of AV conduction during the next cardiac cycle. This results in loss of the next intrinsic depolarization in the ventricle. Generally, this will occur during every-other cardiac cycle. This is commonly referred to as 2:1 AV block. The resulting pattern may be unstable, characterized by intermittent shifts between 2:1 and 1:1 conduction which may offset the other benefits provided by the PESP since ventricular filling is compromised.
What is needed is a system and method that combines the known therapies available for treating cardiac dysfunction including HF in a manner that optimizes mechanical function or cardiac output, while also minimizing any risks associated with possibly inducing an arrhythmia.
As discussed above, PESP therapy involves providing pulses during a non-refractory period of the ventricles. The pulses are delivered such that the ventricles experience a second depolarization some 200-300 ms following an intrinsic or paced depolarization. This results in an extra systole that increases contractile function and stroke volume on subsequent contractions. The magnitude of the enhanced function is dependent on simulation timing. Shorter extrasystolic intervals (ESIs) are known to produce greater potentiation of subsequent cardiac cycles, up to the point when the refractory period is encountered and no additional potentiation results. Likewise, NES therapy involves the delivery of pacing pulses during the refractory period that do not result in a ventricular depolarization, but still result in enhanced cardiac performance.